A5086241411- Axon Guidance and Neuronal Signaling
- Chromatography in Natural Products
- Protein Structure and Dynamics
- Enzyme Structure and Function
- Ubiquitin and proteasome pathways
- Enzyme Production and Characterization
- Computational Drug Discovery Methods
- Genetic Neurodegenerative Diseases
- Neuroscience and Neuropharmacology Research
- RNA Interference and Gene Delivery
- Hepatitis C virus research
- Amyotrophic Lateral Sclerosis Research
- Glycosylation and Glycoproteins Research
- Signaling Pathways in Disease
- Endoplasmic Reticulum Stress and Disease
- Dendrimers and Hyperbranched Polymers
- Mitochondrial Function and Pathology
- Cellular transport and secretion
- Parkinson's Disease Mechanisms and Treatments
- Cancer-related gene regulation
- Protein purification and stability
- Erythrocyte Function and Pathophysiology
- Catalysis for Biomass Conversion
- Hippo pathway signaling and YAP/TAZ
- Seaweed-derived Bioactive Compounds
National University of Singapore
2006-2014
Dalian University
2007
Bioscience (China)
2007
Dalian University of Technology
2007
Significance Transactivation response element (TAR) DNA-binding protein 43 (TDP-43) inclusion is a histological hallmark of FTLD-TDP and amyotrophic lateral sclerosis. Its N terminus was just revealed as double-edged sword indispensable for both physiology proteinopathy, but its structure remains unknown due to aggregation. Here we ( i ) the TDP-43 encodes well-folded in equilibrium with unfolded form; ii despite previous failure detecting sequence homology ubiquitin, folded state assumes...
During tumor progression, EphA2 receptor can gain ligand-independent pro-oncogenic functions due to Akt activation and reduced ephrin-A ligand engagement. The effects be reversed by stimulation, which triggers the intrinsic suppressive signaling pathways of including inhibition PI3/Akt Ras/ERK pathways. These observations argue for development small molecule agonists as potential intervention agents. Through virtual screening cell-based assays, we report here identification characterization...
Dicer or Dicer-like (DCL) protein is a catalytic component involved in microRNA (miRNA) small interference RNA (siRNA) processing pathway, whose fragment structures have been partially solved. However, the structure and function of unique DUF283 domain within dicer largely unknown. Here we report first from Arabidopsis thaliana DCL4. The adopts an α-β-β-β-α topology resembles structural similarity to double-stranded RNA-binding domain. Notably, N-terminal α helix runs cross over C-terminal...
The Eph receptor tyrosine kinases regulate a variety of physiological and pathological processes not only during development but also in adult organs, therefore they represent promising class drug targets. EphA4 plays important roles the inhibition regeneration injured axons, synaptic plasticity, platelet aggregation, likely certain types cancer. Here we report first crystal structure ligand-binding domain, which adopts same jellyroll beta-sandwich architecture as shown previously for EphB2...
Significance FAT10, a ubiquitin-like modifier, is an oncogene that interacts with mitotic arrest-deficient 2 (MAD2) and confers cellular malignancy. Here we identified the MAD2-binding residues of FAT10 determined first solution structure, to our knowledge, domain. Importantly, demonstrated proof-of-mechanism for novel specific drug-targeting strategy entails inhibition pathological activity therapeutic target but not its reported physiological function, thus minimizing undesirable side...
Additional to involvement in diverse physiological and pathological processes such as axon regeneration, synaptic plasticity, cancers, EphA4 receptor has been recently identified the only amyotrophic lateral sclerosis (ALS) modifier. Previously, we found that two small molecules bind same channel at almost equivalent affinities but mysteriously trigger opposite signaling outputs: one activated another inhibited. Here, determined solution structure of 181-residue LBD, which represents first...
The EphA4 receptor tyrosine kinase interacts with ephrin ligands to regulate many processes, ranging from axon guidance and nerve regeneration cancer malignancy. Thus antagonists that inhibit binding could be useful for a variety of research therapeutic applications. In the present study we characterize features three antagonistic peptides (KYL, APY VTM) selectively target among Eph receptors. Isothermal titration calorimetry analysis demonstrated all bind ephrin-binding domain low...
Hepatitis C virus (HCV) affects nearly 200 million people worldwide and is a leading factor for serious chronic liver diseases. For replicating HCV genome, the membrane-associated replication machinery needs to be formed by both non-structural proteins including NS5A human host factors. Recently has been identified bind ER-anchored VAP consequently this interaction may serve as novel target design of anti-HCV drugs. So far no biophysical characterization reported. Here, we dissected...
Eph receptor tyrosine kinases and ephrin ligands control many physiological pathological processes, molecules interfering with their interaction are useful probes to elucidate complex biological functions. Moreover, targeting receptors might enable new strategies inhibit cancer progression angiogenesis as well promote nerve regeneration. Because our previous work suggested the importance of salicylic acid group in antagonistic small receptors, we screened a series derivatives identify novel...
T46I is the second mutation on hVAPB MSP domain which was recently identified from non-Brazilian kindred to cause a familial amyotrophic lateral sclerosis (ALS). Here using CD, NMR and molecular dynamics (MD) simulations, we characterized structure, stability, binding capacity of T46I-MSP domain. The results reveal: 1) unlike P56S previously showed completely eliminate native leads no significant disruption secondary tertiary structures, as evidenced its far-UV CD spectrum, well Cα Cβ...
Insoluble proteins dissolved in unsalted water appear to have no well-folded tertiary structures. This raises a fundamental question as whether being unstructured is due the absence of salt ions. To address this issue, we solubilized insoluble ephrin-B2 cytoplasmic domain and first confirmed using NMR spectroscopy that it only partially folded. Using HSQC titrations with 14 different salts, further demonstrate addition triggers significant folding protein within physiologically relevant ion...
The role of dynamics in protein functions including signal transduction is just starting to be deciphered. Eph receptors with 16 members divided into A- and B- subclasses are respectively activated by 9 B-ephrin ligands. EphA4 the only receptor capable binding all ephrins small molecules overlapped interfaces.We first determined structures ligand domain (LBD) two crystals P1 space group. Noticeably, 8 were found one asymmetric unit consequently from we obtained structures, which show...
Abstract Eph receptors and ephrins constitute the largest family of receptor tyrosine kinases with 15 individual nine ligands. Its ectodomains represent attractive targets not only for understanding fundamental mechanisms underlying axon guidance, cell migration, segmentation, tumorigenesis, bone remodeling, but also drug screening/design to treat cancers, diseases viral infection. So far no NMR study on ephrin is available as such their properties in solution still remain unknown. In this...
Nogo-A has been extensively demonstrated to play key roles in inhibiting central nervous system regeneration, regulating endoplasmic reticulum formation, and maintaining the integrity of neuromuscular junction. In this study, an E3 ubiquitin ligase WWP1 was first identified be a novel interacting partner for both vitro vivo. By using CD, ITC, NMR, we have further conducted extensive studies on all four WW domains their interactions with peptide carrying only PPxY motif. The results lead...
The 16 EphA and EphB receptors represent the largest family of receptor tyrosine kinases, their interactions with 9 ephrin-A ephrin-B ligands initiate bidirectional signals controlling many physiological pathological processes. Most occur between ephrins same class, only EphA4 can bind all A B ephrins. To understand structural dynamic principles that enable Eph to utilize jellyroll β-sandwich fold ephrins, VAPB-MSP domain, peptides small molecules, we have used crystallography, NMR molecular...
Nearly 200 million people are infected by hepatitis C virus (HCV) worldwide. For replicating the HCV genome, membrane-associated machinery needs to be formed both non-structural proteins (including NS5B) and human host factors such as VAPB. Recently, 99-residue VAPC, a splicing variant of VAPB, was demonstrated inhibit replication via binding NS5B, thus acting an endogenous inhibitor infection. So far, structure VAPC remains unknown, its interaction with NS5B has not been biophysically...
Paradoxically, aggregation of specific proteins is characteristic many human diseases and aging, yet aggregates have been found to be unnecessary for initiating pathogenesis. Here we determined the NMR topology dynamics a helical mutant in membrane environment transformed from 125-residue cytosolic all-β MSP by ALS-causing P56S mutation. Unexpectedly, despite its low hydrophobicity, major sperm protein (MSP) domain becomes largely embedded with high backbone rigidity. Furthermore it composed...
<ns4:p>Paradoxically, aggregation of specific proteins is characteristic many human diseases and aging, yet aggregates have been found to be unnecessary for initiating pathogenesis. Here we determined the NMR topology dynamics a helical mutant in membrane environment transformed from 125-residue cytosolic all-β MSP by ALS-causing P56S mutation. Unexpectedly, despite its low hydrophobicity, major sperm protein (MSP) domain becomes largely embedded with high backbone rigidity. Furthermore it...